My career goal is to successfully lead clinical and translational research in the field of traumatic injury and critical care, with the overall intent to improve our understanding of the mechanisms which drive the inflammatory cascade that follows and complicates traumatic injury and to improve the outcomes of those patients who succumb to this inflammatory process. I have the support of a leading Department of Surgery at the University of Pittsburgh, which is uniquely suited for multidisciplinary clinical research, to allow the accomplishment of these goals, and the commitment of an experienced and successful mentor, Dr. Timothy Billiar. Under his mentorship I have assembled a collaborative team with expertise in the inflammatory response post-injury, execution of clinical trials, population genetics, reproductive endocrinology, and biostatistics. Didactic training will complement my research proposal and laboratory experience in each of these disciplines. My research focuses on elucidation of the mechanisms that are responsible for sex based outcome differences following injury. The innate immune response following injury is a complex process whose intensity can be modulated at unique signaling points by different mediators with potential interaction. My preliminary work has helped demonstrate that, in addition to sex-hormone differences, alternative mechanisms including X-chromosome polymorphisms may alter the inflammatory response post-injury and may be responsible for differential outcomes across sex. Based upon these facts, I propose to characterize two plausible mechanisms with sex specific attributes via three parallel aims. First, I will determine if the early sex- hormone milieu following injury is associated with alterations in the innate immune response and important clinical outcomes post-injury. I hypothesize that estrogen will be associated with a protective effect while testosterone will be associated with poor outcome, as has been demonstrated repeatedly in the experimental animal literature. In my second and third aim, I will characterize specific X-chromosome genetic polymorphisms that reside in proteins of the Toll-Like Receptor (TLR) signaling cascade to test the hypothesis if X-linked genetic differences, in concert with sex-hormone differences, are principle determinants of sex based outcome differences following injury. Aim#1 will provide needed understanding regarding the early sex-hormone milieu post-injury and add to the current body of literature where deficits in our understanding currently exist. Aim #2 and Aim #3 will characterize a more novel genetic mechanism as a principal determinant of sex based outcome differences following injury. Aim#2 will investigate a known functional X-linked polymorphism of the TLR pathway (IL-1 receptor-associated kinase-1, IRAK-1), while Aim#3 will characterize polymorphisms of the remaining two X-linked, TLR pathway constituents (Bruton's tyrosine kinase, BTK and NF-:B essential modulator, NEMO), for which no known functional polymorphism evidence currently exists. Together these aims are also designed to provide valuable research experience and training to support my continue evolution towards becoming an independent investigator and a successful clinician scientist. PUBLIC HEALTH RELEVANCE: Relevance for lay audience -Traumatic injury is a major public health problem with an immense societal cost. Despite improvements in trauma management, patients continue to suffer significant morbidity and mortality. Evidence suggests that males and females tolerate severe injury differently with a greater protection afforded to females. Determining the mechanisms responsible for these sex based outcome differences after injury may allow those at highest risk for poor outcome to be predicted and promote interventions that can improve outcomes for all injured patients. The goal of this study is to determine if the early sex hormone environment soon after injury and X-chromosome genetic polymorphisms are responsible for these sex based outcome differences following injury.